The cytotoxicity of the copper chelate of the copper-specific chelating agent 2,8-dimethyl-1,10-phenanthroline to L1210 murine lymphoma cells in vitro had been shown to be due to its marked uptake by these cells. Such uptake was dependent upon the tetrahedral bidentate structure of the copper chelate and resulted in a small but significant in vivo chemotherapeutic activity. Accordingly, we had synthesized the corresponding halomethyl analogs in order to investigate their possible activity as copper-dependent, intercalating alkylating agents. These comprised the series: 2-chloromethyl-9-methyl-1,10-phenanthroline, NSC 382655; 2-bromomethyl-9-methyl-1,10-phenanthroline, NSC 382656; 2,9-bis- (chloromethyl)-1,10-phenanthroline; and 2,9-bis-(bromomethyl)- 1,10-phenanthroline. Copper dependency for cytotoxicity was found only in the monohalomethyl compounds in the range 1 to 3 muM. They were submitted for chemotherapeutic evaluation with a procedure for formulation as cuprous chelates. Copper chelates modulate B16 melanoma growth and metastasis in both a murine strain and copper chelate specific manner. Tumors failed to grow in CDF1 and Swiss mice as subcutaneous transplants unless the mice were pretreated with copper chelates. Thus the cuprous chelate of neocuproine (2,9-dimethyl-1,10-phenanthroline) promoted testicular metastasis in NIH Swiss mice but inhibited them in CDF1 mice, while the nitrolotriacetic acid cupric chelate permitted such metastases in both strains.